Cardiovascular disease (CVD) is the leading Public Health Enemy in the United States. New knowledge is necessary to reduce this burden. Randomized Clinical Trials (RCTs) are considered the gold standard for evaluating the efficacy of a therapeutic intervention and Comparative Effectiveness Trials (CETs) address some of the limitations caused by inclusion and exclusion criteria that may restrict enrollment to a limited group of patients. There is a growing concern in the U.S. that clinical trials reflect only a small percentage of patients with a particular disease, infrequently represent woman and minorities, have a long delay between final trial design and trial initiation, frequently result in prolonged tial recruitment, and often suffer from failure to reach targeted enrollment goals leading to inadequate statistical power and even premature study closure. These factors prevent answering the important questions posed by clinical trials, raising ethical questions around the conduct of experimental research that involves potential risk to patients and the use of scarce resources and limit the ability to translate new knowledge into improved patient care. A replicable formula which has been associated with successful enrollment in the conduct of surgical cardiovascular trials includes a portfolio of pretrial strategies targeted at minimizing enrollment challenges is essential to enrollment efficiency and required in order to reach targeted enrollment goals. A portfolio of pre-trial strategies targeted at minimizing enrollment challenges and tool-kit to be referenced throughout the conduct of a trial include the introduction of innovative components such as the use of social media for patient outreach and webinars as a mechanism to provide information to patients and retain them in trials. iPads with videos and visual images would be used to enhance physician and patient education and training as well as to be used during the informed consent process. The presence of a site champion and frequent communication between the coordinating center and enrollment sites are essential to success. Creative options for trial conduct as well as lessons learned through the performance of RCT's and CET's will be used as a template for recommendations in the decision and conduct of future surgical trials in the CTSN.